Antiproliferative activity of Pt(IV)-bis(carboxylato) conjugates on malignant pleural mesothelioma cells

Our plain-English summary of Antiproliferative activity of Pt(IV)-bis(carboxylato) conjugates on malignant pleural mesothelioma cells, by M. Alessio, I. Zanellato, I. Bonarrigo, et al (Journal of Inorganic Biochemistry, 2013).

The study

• Authors: M. Alessio, I. Zanellato, I. Bonarrigo, E. Gabano, M. Ravera, D. Osella
• Journal: Journal of Inorganic Biochemistry
• Published: 2013;129:52-7
• Cited by: 58 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The bifunctional Pt(IV) conjugate cis,cis,trans-diamminedichloridobis(valproato)platinum(IV), based on the cisplatin square-plane with two axial valproato (2-propylpentanoate, VPA) ligands, has been re-synthesized with a modified procedure and its biological activity was compared with that of its isomer cis,cis,trans-diamminedichloridobis(n-octanoato)platinum(IV). Both complexes showed a striking cytotoxic effect (in the micro or sub-micromolar range) on various human carcinoma cell lines (namely ovarian, colon, breast and lung cancer), and, in particular, on cells derived from malignant pleural mesothelioma. This remarkable activity is due to the action of the cisplatin metabolite only, generated by the intracellular Pt(IV)→Pt(II) reduction, which concentration is greatly increased by the enhanced cellular accumulation of the original, highly lipophilic Pt(IV)-bis(carboxylato) complexes. The two axial VPA ligands are released in a too low concentration to act as histone deacetylase inhibitor (HDACI), as VPA works in the millimolar range, so that no synergism can be claimed. Moreover, n-octanoic acid is substantially deprived of any HDACI propensity.

© 2013.

In plain English

This laboratory study used cell cultures, not people. The authors made two platinum(IV) compounds built around cisplatin, carrying two valproate groups (compound 2) or two n-octanoate groups (compound 3). Valproic acid can block histone deacetylase enzymes; n-octanoic acid essentially cannot. Both were tested for 72 hours on four malignant pleural mesothelioma cell lines, one cisplatin-resistant, on healthy mesothelial cells, and on four other cancer cell lines. The authors wrote that compound 2 was 10 to 50 times more active than cisplatin, but their table shows exceptions: to halve cell viability, compound 2 needed 245 nanomolar versus 19.4 micromolar for cisplatin in the resistant line, and 548 nanomolar versus 4.1 micromolar in the mixed-type line. Compound 3 was 5 to 15 times more potent than compound 2. In sarcomatoid lines, the resistance factor fell from 6.1 (cisplatin) to 1.0 (compound 2). Both compounds accumulated in ovarian and colon cancer cells more than cisplatin. The authors concluded that cisplatin released inside cells, boosted by greater uptake, explained the activity, and that too little valproate was released to inhibit histone deacetylase or produce synergy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study: synthesis of two platinum(IV) compounds and testing of their growth-inhibiting activity and cellular uptake in cultured human cell lines
• Who was studied: Cultured cells. Four malignant pleural mesothelioma (MPM) cell lines: epithelioid BR95, mixed MG06, sarcomatoid MM98, and the cisplatin-resistant sarcomatoid line MM98R. The MPM lines and the healthy cells were obtained from the Hospital of Alessandria, Italy. Also tested: healthy human mesothelial cells (HMC), ovarian A2780, colon HCT116, lung A549 and breast MCF-7 cancer cell lines.
• Exposure: No asbestos exposure was studied. Cells were treated for 72 hours with the drug compounds: compound 2 (two valproato groups) and compound 3 (two n-octanoato groups), with compound 1 and cisplatin as references.
• Main results:
  • The authors stated that compound 2 was 10 to 50 times more active than cisplatin on all the human tumor cell lines tested. Their own Table 1 values do not fit this range for every line (see the next two findings).
  • In the cisplatin-resistant sarcomatoid MM98R line, the concentration halving cell viability (IC50) was 245 ± 53 × 10−9 M for compound 2 and 19.4 ± 2.8 × 10−6 M for cisplatin. This is a larger gap than 50-fold.
  • In the mixed MG06 mesothelioma line, the IC50 was 548 ± 370 × 10−9 M for compound 2 and 4.1 ± 1.5 × 10−6 M for cisplatin. This is a smaller gap than 10-fold.
  • Compound 3 was 5 to 15 times more potent than compound 2 on all nine cell lines tested.
  • For the sarcomatoid mesothelioma cells, the resistance factor (cisplatin-resistant line compared with the original line) was 6.1 for cisplatin and 1.0 for compound 2. The authors read this as absence of cross-resistance.
  • The selectivity index (activity on mesothelioma cells relative to healthy mesothelial cells) rose from cisplatin to compound 2: from 1.1 to 1.4 for epithelioid cells, from 1.6 to 2.2 for mixed cells, and from 2.1 to 5.4 for sarcomatoid cells.
  • After 4 hours, platinum accumulation ratios were higher for compounds 2 and 3 than for cisplatin and compound 1. In A2780 ovarian cells the ratios were 1.5 for cisplatin, 18.6 for compound 2 and 42.4 for compound 3. In HCT116 colon cells they were 2.0, 15.4 and 34.1. Accumulation was measured only in these two cell lines.
  • Adding free valproic acid or n-octanoic acid did not change cisplatin accumulation in A2780 or HCT116 cells.
• The authors' conclusion: The authors concluded that the compounds' activity is essentially due to cisplatin released inside the cells, at a concentration increased by greater uptake of the fat-soluble compounds. They also concluded that the valproate released is too little to inhibit histone deacetylase or to produce synergy.
• Limitations the authors state:
  • The authors' judgment that other uptake routes are unlikely rests on simple tests.
  • The authors note that the better performance of compound 2 applies at least to in vitro (laboratory) tests.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Carcinoma, Lung Cancer.

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